Recent published and unpublished studies from our laboratory suggest aberrant expression of a novel transmembrane mucin, MUC13, in ovarian and pancreatic cancers. We have also shown that exogenous MUC13 expression enhances cellular motility, invasion, proliferation and tumorigenesis of ovarian and pancreatic cancer cell lines. These effects are associated with modulation of HER2 and p53 expression. As supported by our preliminary data, we propose that the overexpression of MUC13 contributes to the pathogenesis of pancreatic cancer. In this grant proposal, our objectives are to delineate the functional aspects of MUC13 mucin in pancreatic cancer. We hypothesize that the different domains of MUC13 execute specific functions in cancer cells and their suppression will diminish pancreatic cancer cell growth and tumorigenesis. Additionally, we hypothesize that the aberrant MUC13 expression operates as an oncoprotein via interaction/stabilization/activation of EGFRs (HER1, HER2) and suppression of p53. To test these hypotheses, we propose three specific aims. 1) To investigate the roles of different MUC13 domains in the function and the signaling pathways modulated by MUC13 in pancreatic cancer cells. 2) To investigate whether the effect of MUC13 on tumorigenesis is mediated through EGFRs (HER1, HER2) and/or the tumor suppressor p53. In this aim we propose to determine if MUC13 physically interacts with EGFRs and/or p53 and influences expression of these proteins. 3) Develop novel methods for targeted repression of MUC13 expression in pancreatic tumors and targeted inhibition of pancreatic cancer cell growth. In this aim we will generate PLGA nanoparticle formulations of MUC13 siRNA and ormeloxifene (an anti- cancer drug), coupled with anti-MUC13 MAbs for their sustained and targeted delivery specifically in pancreatic tumors. Taken together, this information will provide important insights for developing novel therapeutic strategies for pancreatic cancer. PUBLIC HEALTH RELEVANCE: With a very low survival rate, pancreatic cancer is one the most lethal malignancies, primarily due to the lack of early diagnostic markers and limited information regarding the molecular mechanisms surrounding pancreatic cancer. Understanding of the molecular mechanisms of pancreatic cancer progression and the identification of early diagnostic markers may significantly reduce the deaths caused by pancreatic cancer.